tbuckley/cabot-search huggingface dataset:
CTIM-35. A PHASE II STUDY OF GITR AGONIST INCAGN01876 AND PD-1 INHIBITOR RETIFANLIMAB IN COMBINATION WITH STEREOTACTIC RADIOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Stephen Bagley, Jacob Shabason, Divij Mathew, Shawn Kothari, Derek Oldridge, Arati Desai, Robert Lustig, Goldie Kurtz, Michelle Alonso-Basanta, Kan Chen, Qi Long, Jessica Harsch, Muhammad Salman, Peter Fernandez, Maikel Monsour, Timothy Prior, Eileen Maloney, Eileen MacMurtrie, Natalie Angeloni, Meghan O’Neill, Karen Albright, Maria Caturla, Melissa Ignatowski, Suzanne Frangos, Caroline Blessing, Richard Phillips, Ali Nabavizadeh, Suyash Mohan, MacLean Nasrallah, Christina Jackson, Steven Brem, Nduka Amankulor, Zev Binder, Donald O’Rourke, E John Wherry
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND We evaluated the combination of retifanlimab, INCAGN01876, and FSRT in patients with recurrent GBM. METHODS Phase II, single-center, 2 cohort study (A: single-arm non-surgical cohort; B, two-arm neoadjuvant/surgical cohort). Cohort A patients received pre-FSRT one-time doses of retifanlimab (500mg) and INCAGN01876 (300mg), FSRT (8 Gy x 3 fractions), and post-FSRT 28-day treatment cycles (retifanlimab, day 1; INCAGN01876, days 1, 15). Cohort B patients received pre-surgery doses of retifanlimab + INCAGN01876; subsequently, patients either went directly to resection (Sub-Arm 1) or to FSRT followed by resection (Sub-Arm 2). All patients resumed immunotherapy post-operatively. Primary endpoint: ORR in Cohort A. Data cut-off for this analysis was June 30, 2022. RESULTS Thirty-two evaluable patients: Cohort A, n=16; Cohort B, n=16 (Sub-Arm 1, n=8, Sub-Arm 2, n=8). Median follow-up time: Cohort A, 13.6 months; Cohort B, 8.8 months. Forty-four percent women, median age 64 (IQR, 55–65), 56% MGMT unmethylated. Most common grade 3/4 treatment-related AEs included cerebral edema (25%), lymphopenia (16%), and cognitive disturbance (13%). Efficacy in Cohort A: no objective responses observed, best response of stable disease achieved in 9/16 patients (56%), median PFS 3.9 months (95% CI 2.1 – 6.2 months), median OS 9.8 months (95% CI 8.3 months – not reached [NR]). Efficacy in Cohort B: median PFS NR, median OS 15.1 months (95% CI 8.5 months – NR). Median PFS and OS are longer in Cohort B Sub-Arm 2 compared to Cohort B Sub-Arm 1 (PFS, NR vs. 2.2 months, p = 0.009; OS, NR vs. 8.5 months, p=0.026). Results of tissue and blood-based immune correlative analyses will be presented. CONCLUSIONS The combination of retifanlimab, INCAGN01876, and FSRT is generally well-tolerated in patients with recurrent GBM when administered with or without surgical resection. Survival outcomes in the neoadjuvant cohort are encouraging, largely driven by patients that received neoadjuvant FSRT.
PATH-16. THRESHOLDS OF MITOTIC ACTIVITY AND POST-SURGERY RESIDUAL VOLUME ARE INDEPENDENT PROGNOSTIC FACTORS IN ASTROCYTOMA IDH-MUTANT
Authors: Suzanne Tran, Alice Thomas, Mehdi Touat, Carine Karachi, Caroline Dehais, Loïc Feuvret, Karima Mokhtari, Marc Sanson, Ahmed Idbaih, Alexandre Carpentier, Khê Hoang-Xuan, Laurent Capelle, Franck Bielle
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The distinction between grade 2 and 3 is instrumental to choose between observational follow-up and adjuvant treatment in resected astrocytoma IDH-mutant. However, criteria for discriminating grade 2 and 3 tumors have not been updated since the WHO 2007 classification. There is no consensus on the method of evaluation of the mitotic activity or a mitosis cut-off for grading. The objectives were to evaluate the maximal mitotic activity on a series of resected astrocytoma IDH-mutant and assess its prognostic impact on survival. METHODS Maximal mitotic activity on consecutive high-power fields corresponding to 3 mm2 was examined in 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity as well as other prognostic factors (including age, performance status, presurgical tumor volume, plurilobar involvement, postsurgical residual tumor volume, midline involvement) was assessed in tumors with (i) ATRX loss, and (ii) without CDKN2A homozygous deletion, lesional enhancement, histological necrosis nor microvascular proliferation. RESULTS Among the 75 (64%) tumors which had gone through observational follow-up after resection, maximal mitotic activity, post-surgical residual volume and plurilobar involvement were independent prognostic factors of TTT (p &amp;lt; 0.0001). A threshold of mitotic activity for grade 2 was fitted using TTT and OS parameters. Using this threshold, patients with “grade 2 tumors” had a median TTT of 55 months versus 19 months for “grade 3” (p= 0.0057) and a median OS of 102 months versus 73 months respectively (p= 0.001). Residual volume &amp;lt; 1 cm3 was associated with longer OS (113 months versus 88 months, p= 0.0021). CONCLUSIONS The combination of mitotic activity and postsurgical residual volume improves prognostication in resected astrocytoma IDH-mutant. This novel risk assessment method could identify the best candidates for observational follow-up.
EXTH-101. MECHANISTIC INSIGHTS INTO CYTOTOXIC EFFECTS OF LETROZOLE AGAINST GLIOBLASTOMA CELLS
Authors: Aniruddha Karve, Janki Desai, Nimita Dave, Timothy Phoenix, Gary Gudelsky, David Plas, Biplab Dasgupta, Trisha Wise-Draper, Pankaj Desai
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Despite significant advances in multimodal approaches for the treatment of glioblastoma (GBM), the outcome for the patients remains dismal. Previous research from our lab has shown that aromatase (CYP19A1), an enzyme that catalyzes in situ production of estrogens, is markedly elevated in GBM tissues. Additionally, letrozole (LTZ), an aromatase inhibitor with extensive record of efficacious use in breast cancer, exhibited significant activity against GBM in preclinical studies. The purpose of this study was to investigate the mechanism(s) of LTZ activity in GBM. METHODS Patient-derived GBM cells with varying aromatase expression and other genotypic/phenotypic characteristics were employed including aromatase expressing G43, G75, G76, BT-142-gfp-luc and aromatase-null G80 cells. The effects of LTZ on cell viability, neurosphere growth, DNA damage (assessed by measuring phosphorylated histone product ỴH2A.X using flow cytometry) and induction of apoptosis (caspase3/7 activity) were assessed. The effects of exogenous addition of estradiol (E2) was also examined. RESULTS LTZ treatment (72 hours) caused a marked reduction in viability and growth of all GBM cells (IC50 ranging from 0.08 to 0.7 µM) except in G80 cells where LTZ had no effects. LTZ treatment also resulted in inhibition of E2 synthesis in a time and dose-dependent fashion. Furthermore, in aromatase expressing cells LTZ treatment induced apoptosis as measured by increase in Caspase-3/7 activity and triggered significant DNA double strand break as determined by ỴH2A.X formation. The addition of exogenous E2 (250 pg/ml) abrogated the effects of LTZ on cell viability, DNA damage and induction of apoptosis. CONCLUSIONS Our study suggests that the cytotoxic effects of LTZ against GBM are mediated, at least partially, by the inhibition of aromatase activity which results in estrogen deprivation. These mechanistic insights are important to facilitate repurposing LTZ as a novel anti-GBM drug.
NIMG-51. 18KDA TRANSLOCATOR PROTEIN (TSPO) DECLINES IN TUMOR AND IMMUNE CELLS DURING PROGRESSION OF EXPERIMENTAL GLIOBLASTOMA
Authors: Laura Bartos, Sabrina Kirchleitner, Stefanie Quach, Jens Blobner, Karin Wind, Lorraine Weidner, Adrien Holzgreve, Lukas Gold, Lea Kunze, Melissa Antons, Sebastian Kunte, Philipp Beumers, Denise Messerer, Peter Bartenstein, Joerg-Christian Tonn, Louisa von Baumgarten, Markus Riemenschneider, Nathalie Albert, Matthias Brendel
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma combines a lack of immunogenicity with a highly immunosuppressive tumor microenvironment (TME), including both tumor and immune cells. However, biomarkers that allow monitoring of the immune phenotype are still lacking. Hence, we investigated the 18kDa translocator protein (TSPO) during tumor progression in an experiential glioblastoma mouse model (SB28) mimicking human TME. We used TSPO-PET imaging ([18F]GE-180) and in vivo measures of single cell tracer uptake between days 6 and 18 after inoculation to study alterations and dependence of TSPO in tumor and peripheral organs in SB28 mice (n= 27) in comparison to sham controls (n= 11). CSF1R inhibition was applied to deplete tumor associated microglia/macrophages (TAM) followed by withdrawal to induce immune cell rebound (PLX5622 day -20 to day 6, n= 3). Compared to sham, TSPO-PET signals were distinctly elevated in tumor (+83%, p&amp;lt; 0.001), heart (+35%, p&amp;lt; 0.05), lung (+42%, p&amp;lt; 0.01) and bone (+26%, p&amp;lt; 0.05) of SB28 mice at day 6. TSPO-PET increases were lower at day 18 (tumor: +52%, p&amp;lt; 0.05; all organs &amp;lt; +15%, n.s.). The tumor TSPO-PET signal was strongly coupled with TSPO-PET signal in peripheral organs (all R≥ 0.88, all p&amp;lt; 0.001). Single tumor cells and TAM showed strong early increases of TSPO tracer uptake at day 6 (tumor: 32-fold, TAM: 8.5-fold) and a decline of these increases at day 18 (tumor: 2.4-fold, TAM: 1.7-fold) when compared to sham microglia. Immune cell rebound restored TSPO tracer uptake in TAM (+120%, p&amp;lt; 0.01) but not in tumor cells (-24%, n.s.) when compared to therapy-naïve SB28 mice. TSPO declines in tumor cells and TAM during progression of experimental glioblastoma. TSPO in peripheral organs could serve as a supportive indicator of declining immune response in glioblastoma. CSF1R inhibition and reinitiation yields specific restoring of TSPO in TAM and could serve as immunomodulatory therapy strategy.
TMIC-47. SINGLE-CELL TRANSCRIPTOMICS REVEALS ANTITUMOR IMMUNE RESPONSES OF PROTON TREATMENT IN GLIOBLASTOMA
Authors: Kalen Berry, Sean Ogurek, Rohit Rao, Richard Lu
Journal: Neuro-Oncology (2022)

Abstract Proton therapy is an innovative radiation therapy modality that has been shown to induce higher cytotoxicity to tumor cells compared to standard x-ray therapy while sparing normal tissue. However, the impact of proton radiotherapy on the growth and progression of glioblastoma (GBM) has not been defined. We hypothesize that understanding tumor evolution and micro environmental responses to radiotherapy is critical for developing and targeting interventions. In this study, we investigate the effect of proton versus standard photon radiotherapy on tumor growth and the microenvironment in an orthotopic syngeneic GBM model over the course of treatment. We characterized tumor tissues at early, progressing, and terminal phases post irradiation by single cell transcriptomics, bulk RNA sequencing, and histology. We find that proton irradiation led to a drastic reduction in tumor volume at early stages before eventual recurrence. Proton treatment exhibits equivalent if not superior, tumor control when compared to normal photon radiation. Single cell transcriptomics analyses show a dramatic increase in immune cell populations including T cell and macrophage populations which peak shortly before tumor recurrence. In addition, we identify an increase in exhausted T cell markers such as PD1, Tim-3, and Lag-3 in T cells post irradiation. Treatment with therapeutic agents that reprogram microglia/macrophages to an anti-tumor phenotype and activate T cell effector functions effectively eradicate GBM recurrence post irradiation. Thus, our study demonstrates a powerful combined treatment strategy with radiation against GBM and provides valuable information about how tumor growth and microenvironment respond to proton therapies, as well as potential mechanisms of tumor response and recurrence in GBM.
CNSC-11. T-TYPE CALCIUM CHANNELS DRIVE GLIOBLASTOMA GROWTH BY PROMOTING NEURONAL INTERACTIONS
Authors: Collin Dube, Ying Zhang, Shekhar Saha, Michelle Lai, Myron Gibert, Miguel Escalante, Elizabeth Mulcahy, Matteo Ottolini, Kadie Hudson, Ulas Yener, Sylwia Bednarek, Farina Hanif, Esther Xu, Aditya Sorot, Swapnil Sonkusare, Harald Sontheimer, Roger Abounader
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor with a dismal median survival of 15 months. Calcium signaling regulates a plethora of cellular processes making it an ideal target for therapeutic intervention. T-type calcium channels (TTCCs) are low voltage gated calcium channels expressed in various types of neurons throughout the brain regulating glutamatergic synaptic transmission. Our group identified T-type calcium channels as upregulated in GBM cells, stem cells and human tumors. Utilizing an FDA repurposed TTCC blocker mibefradil we demonstrated that inhibition of TTCCs decreases GBM malignancy parameters. To further elucidate the mechanisms of action of TTCC, we treated glioma stem cells (GSCs) with mibefradil followed by RNA-sequencing. Analysis of the transcriptome revealed that mibefradil downregulated genes associated with neuronal processes including synapse organization, postsynaptic density and glutamatergic synapses. The effects of TTCC inhibition on neuronal processes led us to examine the role of neuronal TTCC in promoting GBM growth. Genetic loss of TTCC, Cav3.2 via knockout (KO) in the microenvironment of mice xenografted with syngeneic cell lines exhibited delayed tumor progression. Cav3.2 KO mice exhibited a 5.5-fold reduction in tumor volume as measured by MRI and an increase in survival compared to WT mice. Cav3.2 KO tumors exhibited a decrease in proliferation measured by Ki67+ cells compared to WT mice. Cav3.2KO tumors exhibit fewer connections between tumor cells and neurons as measured by immunofluorescence. To further test the roles of neuronal Cav3.2 in GBM, we isolated WT and Cav3.2KO neurons for neuron-GBM co-cultures. Cav3.2KO neuron-GBM co-cultures exhibited a significant decrease in proliferation compared to WT neuron-GBM co-cultures. Additionally, Cav3.2KO neuron-GBM co-cultures exhibited a decrease in synaptic connections and a decrease in neuronal projections to GBM cells compared to WT neuron-GBM co-cultures. These data uncover a new role for TTCC Cav3.2 in promoting neuron-GBM interactions and GBM growth.
NCOG-29. INFLUENCE OF RADIATION DOSES TO HIPPOCAMPAL SUBVOLUMES ON MEMORY OUTCOMES IN PITUITARY TUMORS: DOES THE ENTIRE HIPPOCAMPUS NEED TO BE SPARED?
Authors: Archya Dasgupta, Ajay Thomas, Arpita Sahu, Ujjwal Agarwal, Abhishek Chatterjee, Savita Goswami, Utpal Gaikwad, Vikas Singh, Prakash Shetty, Aliasgar Moiyadi, Ayushi Sahay, Epari Sridhar, Rakesh Jalali, Tejpal Gupta, Jayant Sastri Goda
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION In patients treated with radiation (RT), doses to hippocampus influence neurocognitive outcomes. However, the role of hippocampal subvolumes in memory functioning has not been reported, which prompted the current study. METHODS Adults ( &amp;gt; 18 years) with pituitary tumors treated with fractionated RT (45 Gy/ 25 fractions/ 5 weeks) were accrued in the prospective study. Hippocampus was delineated on T1-weighted 3D-FSPGR sequences with 1mm slice thickness. The head, body, and tail of hippocampus were drawn for the current study based on the consensus of two neuroradiologists. The anatomical landmarks were: head (basilar artery to interpeduncular cistern), body (interpeduncular cistern to superior colliculus), and tail (beyond superior colliculus). Memory assessment was done pre-RT and 18 months post-RT by dedicated neuropsychologist using Weschler Memory Scale. The dose-volume parameters (maximum, mean, D10-D100) were extracted from bilateral hippocampus and subvolumes individually, which were correlated with the memory outcomes. Binary endpoints of &amp;gt; 5% drop of memory quotient (MQ) or not at 18 months were used for analysis using an independent t-test or Mann Whitney test as appropriate. RESULTS Of 25 patients included in the analysis, 11 had drop of MQ &amp;gt; 5% at 18 months. The left and right hippocampus doses of D10, D20, and D30 were significantly higher in patients with higher memory decline. For the subvolumes, only dose to bilateral head had statistically significant impact on MQ. Mean doses for patients with &amp;gt; 5% MQ drop for left and right heads were 26 Gy and 24 Gy compared to 21 Gy and 19 Gy, respectively, for the other group. CONCLUSION Doses to bilateral hippocampus were shown to impact short-term memory. Of the subvolumes, only head appeared significant in memory functioning from the current pilot study, opening a window for exploring stricter dose constraints towards hippocampal head for primary or metastatic brain tumors.
CSIG-23. ALTERATIONS IN THE TRANSSULFURATION PATHWAY DRIVE GLIOBLASTOMA INVASION IN THE PERITUMORAL WHITE MATTER
Authors: Joseph Garcia, Saket Jain, Erin Akins, Luis Carrete, Allison Zheng, Sabraj Gill, Sanjay Kumar, Manish Aghi
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma is the most common and lethal adult brain tumor with a median survival under two years. The poor prognosis glioblastoma carries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Although numerous molecular factors have been proposed as driving glioblastoma invasion, the search for targetable pathways to mediate glioblastoma invasion has been largely unfruitful. Despite a well-established relationship between metabolic reprogramming and cancer cell survival, little attention has been paid to the metabolic alterations needed for invading tumor cells to thrive in peritumoral white matter. To address this knowledge gap, we defined the links between tumor metabolism and invasion using metabolomics, transcriptomics, and CRISPR screens in biomimetic 3D hydrogels and regional biopsies of patient glioblastomas. Metabolomic and lipidomic screening of 315 metabolites and 691 lipids revealed cystathionine, a cysteine precursor in glutathione synthesis in the transsulfuration pathway, as well as hexosylceramides and glucosyl-ceramides, which counteract oxidative stress, to be enriched in invasive tumor cells in hydrogels and patient samples. Immunostaining confirmed elevated secondary ROS markers in invasive GBM cells in hydrogels and patient specimens. While adding ROS promoted GBM invasion in hydrogels, ROS sequestration had no effect. A CRISPR screen of 3000 metabolic genes revealed cystathionine gamma lyase (CTH), which catalyzes the last step in the transsulfuration pathway, to be essential for glioblastoma invasion. Genetic and pharmacologic CTH inhibition suppressed glioblastoma invasion in hydrogels in a manner rescued by exogenous cysteine. Thus, invasive glioblastoma cells exhibit high ROS levels, metabolic adaptations to ROS, and increased invasion in response to ROS. While targeting ROS directly did not slow invasion, targeting metabolic adaptations to ROS in the transsulfuraton pathway suppressed invasion. Our work defines the first link between metabolic adaptations and glioblastoma invasion, intriguing findings warranting future exploration.
NIMG-14. RADIOLOGIC ASSESSMENT OF BRAIN METASTASES UNDERGOING LASER INTERSTITIAL THERMAL THERAPY (LITT)
Authors: Francesco Sanvito, Raksha Nagaraj, Jessica T Sayari, Shivam Rana, Catalina Raymond, Nicholas S Cho, Khashayar Mozaffari, Ansley Unterberger, Isaac Yang, Benjamin Ellingson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Laser Interstitial Thermal Therapy (LITT) is a novel treatment for brain metastases (BMs), and data regarding radiologic changes and long-term efficacy is sparse. This study explored volumetric changes in responding and non-responding BMs and their associations with lesion-specific progression-free survival (PFS-L). METHODS Patients with BMs treated with LITT were retrospectively enrolled. 3D volumes-of-interest of the contrast-enhancing BM tissue (CE) on pre-, post-LITT, and follow-up MRI scans were obtained. BMs were followed until progression or censoring. PFS-L was determined using the modified RANO criteria to assess treatment efficacy on each lesion. RESULTS Thirty-one BMs (from 30 patients) were preliminarily analyzed. 2 BMs had no follow-up scans. Median follow-up for 29 BMs was 248 days (range 28-2200). Median time to response was 430 days (responders n=7/29), median time to progression was 176 days (progressive disease n=7/29). Pre-LITT CE volume was a predictor of PFS-L (p=0.001), with BMs&amp;gt; 2.5 cc being 14 times more likely to undergo progression. Differences in age and primary tumor site did not impact PFS-L, whereas PFS-L tended to be longer in females (p=0.059), and in frontal and deep grey matter BMs (p=0.11). Post-LITT CE volume was higher than pre-LITT (p&amp;lt; 0.0001, median increase 59%), with no significant differences among responders, stable disease, and progressive disease. In each responding BM, the CE volume shrinkage over time was described by an exponential decay (R2 ranging 0.92-1.0 and half-life ranging 16.55-204 days). All responding BMs showed a pooled exponential decay with R2=0.88 and half-life=75.6 days. CONCLUSIONS Our data suggest that smaller BMs may have improved outcomes from LITT treatment. CE volumes may increase in the early post-procedural scans, possibly due to both inflammatory changes and thermal damage. The characterization of the volumetric changes across time for responding lesions may be useful for an early detection of BMs at risk for progression.
CTNI-50. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB/OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: UPDATED RESULTS
Authors: Annie Hsieh, Elizabeth Gerstner, Solmaz Sahebjam, David Piccioni, Jian Campian, Jan Drappatz, Robert Aiken, Eudocia Lee, Mary Welch, Kevin Becker, Mickey Williams, Christopher Karlovich, Alona Muzikansky, Pierre Giglio, Percy Ivy, Tracy Batchelor, Isabel Arrillaga-Romany
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Hypoxia from inhibition of angiogenesis reduces DNA repair capacity. Targeting homologous recombination pathway also has anti-angiogenic effects. To examine the synergistic effects of disrupting DNA repair pathways and angiogenesis in glioblastoma, we combine cediranib (ced), a pan vascular endothelial growth factor (VEGF) receptor inhibitor with olaparib (ola), a poly-ADP ribose polymerase (PARP) inhibitor compared with bevacizumab (bev), a VEGF-A inhibitor alone. To identify potential biomarkers predicting response to treatments, we also perform whole exome sequencing on archival tissues. METHODS Bevacizumab-naïve adult patients with first or second recurrence of glioblastoma after radiation and temozolomide were randomly assigned to cediranib (30mg PO daily)/olaparib (200mg PO twice daily) or bevacizumab (10mg/kg IV every 2 weeks). The primary end point was progression-free survival (PFS) at 6 months. The secondary end points included safety and overall survival (OS). Whole exome sequencing of formalin-fixed paraffin embedded archival tissue from 23 patients was performed. RESULTS We are presenting the final data from this trial. Between December 2017 and November 2018, a total 70 adult patients with recurrent glioblastoma were randomly assigned to receive ced/ola (n = 35) or bev (n = 35). With a data cut off on 5/30/2022, median PFS was 118 days and 92 days in ced/ola and bev groups, respectively (hazard ratio, 1.099, 95% CI 0.6-2, p = 0.76). Median overall survival was 269.5 days and 192 days in ced/ola and bev groups, respectively (hazard ratio, 0.6892, 95% CI 0.39-1.2, p = 0.2). Whole exome sequencing was performed in total 23 patients (24 samples), 14 patients in the ced/ola group and 9 patients in the bev group. CONCLUSION No significant survival benefit was observed in patients with recurrent glioblastoma treated with ced/ola compared to patients treated with bev monotherapy. Potential biomarkers predicting response to treatment identified from the whole exome sequencing on archival tissues will be presented.